Wang Tony, Blatt Lawrence M, Seiwert Scott D
InterMune Inc., Brisbane, CA 94005, USA.
J Interferon Cytokine Res. 2006 Jul;26(7):473-83. doi: 10.1089/jir.2006.26.473.
The standard of care for chronic hepatitis C, pegylated interferon-alpha (IFN-alpha) and ribavirin (RBV), causes a sustained virologic response (SVR) in approximately 50% of patients. SVR is correlated with innate and adaptive immune system responses, such as natural killer (NK) cell activation, production of IFN-alpha from immature plasmocytoid dendritic cells (pDC), and polarization of CD4(+) cells to a T helper 1 (Th1) cell phenotype. To examine how these immunologic responses vary with currently available regimens for chronic hepatitis C, cell populations purified from human peripheral blood mononuclear cells (PBMC) were treated with the clinically available combinations of pegylated IFN-alpha2b (PEG-IFN-alpha2b) + RBV, IFN-alphacon1 + RBV, or IFN- alphacon1 + IFN-gamma1b, and activation of cellular immune system components was monitored. The magnitude of NK cell activation depended on regimen, with IFN-alphacon1 + IFN-gamma1b > IFN-alphacon1 + RBV > PEG-IFN- alphaa2b + RBV. The maximum human serum concentrations of IFN-alphacon1 + IFN-gamma1b saturated NK cell activation, whereas the maximum human serum concentrations of IFN-alphacon1 + RBV or PEG-IFN-alpha2b + RBV did not. IFN-gamma1b also enhanced the production of IFN-alpha from immature pDCs, which are the dominant source of IFN-alpha upon viral infection. The rank order for induction of Th1 cell phenotype and repression of Th2 cell phenotype by the cocktails described was identical to that observed for NK cell activation. Additionally, IFN- gamma1b suppressed the ability of the hepatitis C virus (HCV) NS4 protein to enhance monocyte secretion of interleukin- 10 (IL-10), a cytokine whose expression level is correlated with viral persistence. These results suggest that addition of IFN-gamma1b to HCV treatment regimens may provide unique benefits.
慢性丙型肝炎的标准治疗方案，聚乙二醇化干扰素-α（IFN-α）和利巴韦林（RBV），在大约50%的患者中可引起持续病毒学应答（SVR）。SVR与先天性和适应性免疫系统应答相关，如自然杀伤（NK）细胞活化、未成熟浆细胞样树突状细胞（pDC）产生IFN-α，以及CD4(+)细胞向辅助性T细胞1（Th1）细胞表型极化。为了研究这些免疫应答如何随目前可用的慢性丙型肝炎治疗方案而变化，用临床可用的聚乙二醇化IFN-α2b（PEG-IFN-α2b）+RBV、IFN-αcon1+RBV或IFN-αcon1+IFN-γ1b组合处理从人外周血单个核细胞（PBMC）中纯化的细胞群体，并监测细胞免疫系统成分的活化情况。NK细胞活化的程度取决于治疗方案，IFN-αcon1+IFN-γ1b＞IFN-αcon1+RBV＞PEG-IFN-α2b+RBV。IFN-αcon1+IFN-γ1b的最大人血清浓度可使NK细胞活化饱和，而IFN-αcon1+RBV或PEG-IFN-α2b+RBV的最大人血清浓度则不能。IFN-γ1b还增强了未成熟pDC产生IFN-α的能力，未成熟pDC是病毒感染时IFN-α的主要来源。所述鸡尾酒疗法诱导Th1细胞表型和抑制Th2细胞表型的顺序与NK细胞活化观察到的顺序相同。此外，IFN-γ1b抑制丙型肝炎病毒（HCV）NS4蛋白增强单核细胞分泌白细胞介素-10（IL-10）的能力，IL-10是一种细胞因子，其表达水平与病毒持续存在相关。这些结果表明，在HCV治疗方案中添加IFN-γ1b可能会带来独特的益处。
